1. Field of the Invention
The present invention relates to the noninvasive assessment of the electrical and hemodynamic state of the brain. More particularly, the present invention relates to assessment by monitoring of intracranial pressure.
2. Description of the Related Art
Traumatic brain injury (TBI) is among the leading causes of death and disability in the US, with more than 1.4 million new incidents every year, leading to 235,000 hospitalizations and 50,000 deaths and attributing to $60 billion in direct and indirect medical costs. Moreover, it is estimated that over 5 million Americans have a permanent disability as a consequence of TBI. Clinical presentation and ultimate consequences of TBI are variable and dependent on the severity, extent, and localization of the injury, as well as on the promptness and adequacy of the care provided to the injured. Three conditions, often occurring in concert, are identified as particularly detrimental: silent (non-convulsive) seizures, decreased cerebral blood flow (ischemia), and increased intracranial pressure.
Silent Seizures:
Non-convulsive (or silent) seizures refer to epileptic attacks that do not involve the motor cortex, and subsequently do not result in muscle activity (as opposed to convulsive seizures, that manifest in twitches, cramps, prolonged (tonic) muscle contractions or the like). Silent seizures have been documented to occur frequently after traumatic or a variety of hemorrhagic injuries to the brain. The incidence of silent seizures increases as a function of the severity of injury, and other selected features of the injury such as the presence of hemorrhagic contusions. In recent years it has been convincingly demonstrated that non-convulsive seizures adversely affect the prognosis after brain insults by increasing the metabolic demands of the brain in a situation when cerebral blood flow is usually already compromised. While the treatment of silent seizures (with standard anti-epileptic drugs) is rather efficient, their detection remains the weakest point in the acute care of patients; they are impossible to detect upon standard clinical examination, and can only be revealed if the electrical activity of the brain is recorded (e.g., using an electroencephalographic (EEG) recorder). EEG is however infrequently recorded in most neuro-intensive care units because of the difficulties in using relatively bulky EEG systems in a crowded setting of an ICU, and in maintaining good electrical contact between the EEG electrodes and the scalp of the patient over longer periods of time.
Silent seizures can be detected from the continuously recorded EEG by either displaying the EEG signal to a trained human expert (typically a neurologist) or by submitting the recorded EEG signal to signal processing algorithms and/or classifiers designed to recognize and extract features (e.g. spikes, spike-and-wave complexes) indicative of an ongoing epileptic seizure. The first approach is essentially the only one used in the clinical practice, and it belongs to the public domain. The second approach is still largely limited to experimental settings, but with further improvements in computational technologies and artificial intelligence it may find its way to clinicians. Methods for automated detection of seizures have been disclosed in various patents, with some methods assuming the use of a portable EEG recording device and other methods assuming that any EEG recording device or system can be used for patient monitoring.
Cerebral Blood Flow and Detection of Ischemia:
Cerebral blood flow (CBF) is frequently compromised following a traumatic brain injury (TBI) due to a variety of reasons: direct damage to intracranial blood vessels, hypotension caused by concomitant hemorrhage, vasospasm caused by vasoactive substances released from the damaged brain tissue, or increased intracranial pressure (ICP). Decreased CBF can cause a secondary, ischemic brain injury, that is often more severe and extensive than the primary injury inflicted in an accident. However, standard methods for measuring CBF are technically complex, financially costly, and are applied in specialized institutions where the equipment and knowledge are available. See Table 1. Some of the methods from Table 1 belong to the public domain and some are disclosed in various patents. For example, in some patents, CBF is estimated from ultrasound measurements. In other patents, CBF is derived from near-infrared spectroscopy (NIRS) measurements after administration of an intravascular contrast (dye). In still other patents, a combination of EEG, rheoencephalography (REG) and peripheral physiological signals (such as EKG and pulse oximetry) can be used to estimate the cerebral blood flow and differentiate patients with atherosclerosis from healthy individuals. However, these methods are focused on only measuring the flow through the arterial portion of the cerebral vasculature.
TABLE 1Methods for measurement of CBFMethodsShortcommings for in-field useNitrous oxide inhalationCumbersome, unsuitable for dynamicmethodchangesO215 positron emissionRadioactive, expensive, not portabletomography (PET)Single photon emissionRadioactive, expensive, not portabletomography (SPECT)Perfusion-weighted MRIExpensive, not portableXe-enhanced computerizedRadioactive, expensive, not portabletomography (CT)Transcranial Doppler (TCD)Considerable expertise requiredIntracranial probes (basedInvasive, risk of infections, noton laser flowmetry)absolute measurement
In accordance with principles of the present invention, the methods disclosed herein teach the use of rheoencephalography (REG) and optical measurements (e.g., near-infrared spectroscopy) for the assessment of cerebral blood flow and blood volume in the arterial and venous portion of the cerebral vasculature.
REG denotes a measurement of the electrical impedance of the head to the passage of an alternating current of low amplitude (˜2 mApp) and relatively high frequency (˜20-150 kHz). As blood is a much better conductor of electricity at these frequencies than most other tissues that compose the head, the measured impedance varies with the pulsatile flow of blood. See FIG. 1A. Changes in the morphology of the REG waveform such as the peak amplitude, rise time to peak amplitude, and appearance of the descending limb have been shown to reflect changes in cerebral blood volume and flow in a variety of conditions including experimental hemorrhage, post-traumatic contusions, cerebral atherosclerosis, and other cerebral vasculopathies. See FIG. 1B.
Near-infrared spectroscopy (NIRS) refers to a measurement in which light at wavelengths 760-1400 nm (near-infrared range) is delivered to a body part at one point, and the amount of light that is transmitted through the body part is measured with a light sensor located at another point at some distance from the point where the light emitter is located. See FIG. 2A. In cases where the brain is an object of the measurements, several light emitters and sensors organized into a grid are typically utilized. See FIG. 2B.
Although the light is to some extent absorbed by all tissues lying on its path (e.g., skin, bone, cerebrospinal fluid, brain tissue, blood), the absorption caused by blood can be easily separated from the other tissues due to its pulsatile nature. For example, three types of pulsations can be found in the raw NIRS signal: arterial pulsations synchronous with cardiac cycles (typical frequency: 40-200 per minute), venous pulsations synchronous with respiration (typical frequency: 8-20 per minute), and so-called “Meyer oscillations” that are synchronous with slow blood pressure changes caused by sympathetic stimulation (typical frequency: less than 5 per minute). Clinical applications of the NIRS have so far focused mostly on the arterial pulsations, utilizing their amplitude to derive cerebral tissue oxygenation, cerebral blood volume and blood flow, or detect intracranial hematomas and brain edema. Recently, however, venous pulsations in the NIRS signal have been used to measure cerebral venous oxygenation in neonates and adults.
In comparing the two methods (REG and NIRS) the following should be noted: while both NIRS and REG detect arterial pulsations, and are subsequently capable of monitoring cerebral blood volume and flow in the arterial portion of the vasculature, NIRS has an advantage of revealing information about the venous portion of the vascular bed. However, since the near-infrared light penetrates only 5-10 mm into the head, NIRS can only monitor blood flow in the brain cortex but not in the deeper structures. REG on the other head does not make a distinction between the cortex and deeper structures as both have similar electrical conductance.
Intracranial Pressure:
Intracranial pressure (ICP), or the pressure inside of the skull, is usually altered following a traumatic brain injury or hemorrhagic insult, as these conditions lead to volume expansion in a rigid and non-expandable skull (due to blood collections inside of the skull, or brain edema, etc.). Once ICP increases over 20 mHg a vicious cycle easily develops in which the increased ICP decreases cerebral blood flow, leading to brain tissue ischemia that results in edema, which through a volume expansion further increases ICP. The ultimate effect is a severe decrease in cerebral blood flow (CBF) with consequent brain tissue hypoxia and death of affected neurons. Consequently, monitoring of the ICP and preventing its increase are fundamental in treatment of conditions such as traumatic brain injury, stroke, and spontaneous intracranial hemorrhage.
The gold standard technique for ICP monitoring is an invasive procedure that involves inserting a fluid-filled catheter into the intracranial compartment, and connecting it to a standard pressure transducer. Alternatively, micro-transducer-tipped ICP probes can be inserted in the brain parenchyma or subdural space through a skull bolt or small burr hole. Other methods such as subarachnoid and epidural transducers or spinal tap have much lower accuracy. However, the invasive methods for monitoring ICP share several common drawbacks: the transducers have to be calibrated before insertion; their output drifts, requiring either a recalibration or replacement of the catheter after 36-48 hours; insertion of a catheter carries a risk of brain or spinal cord damage and infection; and the placement of a catheter requires a highly trained individual, such as a neurosurgeon. For these reasons, invasive ICP monitoring techniques cannot be used outside of the hospital setting.
Non-invasive methods of measuring ICP are disclosed in Popovic et al., “Noninvasive Monitoring of Intracranial Pressure,” Recent Patents on Biomedical Engineering 2(3):1-15 (2009). Table 2, shown below, is reproduced from U.S. Pat. No. 5,617,873, US20016231509, US20026413227, U.S. Pat. No. 4,984,567, U.S. Pat. No. 4,971,061, WO00068647, U.S. Pat. No. 5,919,144, U.S. Pat. No. 5,388,583, US20026457147, US20046761695, U.S. Pat. No. 5,993,398, US20006086533, US20067104958, U.S. Pat. No. 5,951,477, U.S. Pat. No. 5,074,310, U.S. Pat. No. 5,117,835, US20006117089, US20046746410, US20046740048, US20046773407, U.S. Pat. No. 5,993,398, U.S. Pat. No. 4,564,022, U.S. Pat. No. 4,841,986, US20067147605, US20036589189, WO98034536, US20026390989, US20067122007, US20060206037, and U.S. Pat. No. 4,204,547, herein incorporated by reference.
TABLE 2Comparison of methods for noninvasive monitoring of ICPAccuracySkill level(SE ofrequiredCost ofContinuousOther advantages Method measurement)for usetechnologymonitoringor shortcomingsUltrasound±10 mmHgLowModerateYesEasily portable andtime of flightfield-deployableTranscranial±10 mmHgExpertModerateNoFinding correctDopplervessels difficulteven for expertsAcousticNot validatedLowLow /PossibleEasily portable andproperties ofmoderatefield-deployablecranial bonesEEGNot validatedModerateModerateNoRepeated visualstimulation neededCumbersomeMRINot validatedExpertHighNoNot a bedsideassessmentTympanic±10-15 mmHgModerateLowNoInapplicable inmembraneolder patientsdisplacementOtoacoustic±10-15 mmHgModerateLowNoInapplicable inemissionolder patientsONSD±5-10 mmHgModerate/HighModerateNoOphthalmo-±2-3 mmHgExpertLowNo CumbersomedynamometryJugular bloodNot validatedExpertLow /NoCumbersomeflow velocitymoderateUnpleasantmeasurement
Table 2 illustrates that the non-invasive methods' common drawback is insufficient accuracy: the margins of error of ICP estimates are of the same order of magnitude as the whole range of ICP that is clinically of interest (0-50 mmHg). The noninvasive methods can therefore reliably identify only subjects with low to normal or very high ICP, but not the clinically most important population with moderately increased ICP (15-30 mmHg).
The present invention seeks to overcome the deficiencies described above.